PPAR Alpha Activation by Clofibrate Alleviates Ischemia/Reperfusion Injury in Metabolic Syndrome Rats by Decreasing Cardiac Inflammation and Remodeling and by Regulating the Atrial Natriuretic Peptide Compensatory Response

Abstract

Metabolic syndrome (MetS) is a cluster of factors that increase the risk of developing diabetes, stroke, and heart failure. The pathophysiology of injury by ischemia/reperfusion (I/R) is highly complex and the inflammatory condition plays an important role by increasing matrix remodeling and cardiac apoptosis. Natriuretic peptides (NPs) are cardiac hormones with numerous beneficial effects mainly mediated by a cell surface receptor named atrial natriuretic peptide receptor (ANPr). Although NPs are powerful clinical markers of cardiac failure, their role in I/R is still controversial. Peroxisome proliferator-activated receptor α agonists exert cardiovascular therapeutic actions; however, their effect on the NPs’ signaling pathway has not been extensively studied. Our study provides important insight into the regulation of both ANP and ANPr in the hearts of MetS rats and their association with the inflammatory conditions caused by damage from I/R. Moreover, we show that pre-treatment with clofibrate was able to decrease the inflammatory response that, in turn, decreases myocardial fibrosis, the expression of metalloprotease 2 and apoptosis. Treatment with clofibrate is also associated with a decrease in ANP and ANPr expression.

Identifying therapeutic target genes for migraine by systematic druggable genome-wide Mendelian randomization

“…An animal study has shown that clofibrate can improve oxidative stress and neuroinflammation caused by the exaggerated production of lipid peroxidation products [ 54 ]. Clofibrate can activate peroxisome-proliferator-activated receptors (PPAR) α, inhibit the activation of the NF-κB signaling pathway and the production of interleukin (IL)-6, exerting an anti-inflammatory effect [ 55 , 56 ]. Additionally, a recent animal study indicated the upregulation of astrocytic activation and glial fibrillary acidic protein (GFAP) expression in the trigeminal nucleus caudalis (TNC) in migraine mice model induced by recurrent dural infusion of inflammatory soup (IS).…”

Targeting myocardial inflammation: investigating the therapeutic potential of atrial natriuretic peptide in atrial fibrosis

“…Inflammatory factors are direct inducers of atrial fibrosis, suggesting that inhibiting myocardial inflammation could be a viable strategy to reverse atrial fibrosis. The anti-inflammatory effect of ANP has been observed in various animal models, showing alleviation of inflammation in tissues like the pancreas, colon, and myocardium [37][38][39]. Clinical studies have indicated that ANP infusion can mitigate spontaneous inflammation following myocardial infarction, reducing ventricular fibrosis and counteracting adverse ventricular remodeling [19].…”

Sıçanlarda sirkadiyen ritim bozuklukları ile ilgili çeşitli koşulların plazma ve eritrosit lipidleri üzerindeki etkileri: peroksizomal bir bakış açısı

“…On the contrary, fenofibrate supplementation produced no noticable hydropic changes in liver tissue sections. PPAR alpha agonists are known to suppress inflammatory events via the NF-κB pathway and inhibit ROS production [23,24], Therefore, it is possible that damaging effect of hydrogen peroxide by-product of peroxisomal oxidation activity might have been served as an offset through antioxidant and antiinflammatory action of fibrates.…”